Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers

Abstract

Papillary thyroid cancers (PTCs) incidence dramatically increased in the vicinity of Chernobyl. The cancer-initiating role of radiation elsewhere is debated. Therefore, we searched for a signature distinguishing radio-induced from sporadic cancers. Using microarrays, we compared the expression profiles of PTCs from the Chernobyl Tissue Bank (CTB, n=12) and from French patients with no history of exposure to ionising radiations (n=14). We also compared the transcriptional responses of human lymphocytes to the presumed aetiological agents initiating these tumours, gamma-radiation and H(2)O(2). On a global scale, the transcriptomes of CTB and French tumours are indistinguishable, and the transcriptional responses to gamma-radiation and H(2)O(2) are similar. On a finer scale, a 118 genes signature discriminated the gamma-radiation and H(2)O(2) responses. This signature could be used to classify the tumours as CTB or French with an error of 15-27%. Similar results were obtained with an independent signature of 13 genes involved in homologous recombination. Although sporadic and radio-induced PTCs represent the same disease, they are distinguishable with molecular signatures reflecting specific responses to gamma-radiation and H(2)O(2). These signatures in PTCs could reflect the susceptibility profiles of the patients, suggesting the feasibility of a radiation susceptibility test.

Figure 1

IRIBHM vs Jarzab et al. (2005) microarray data. Pearson correlation between patient-averaged log₂ tumour/normal ratios of the two studies is 0.72.

Figure 2

Global expression profiles. Top panel: hierarchical clustering on the basis of all genes. Bottom panel: multidimensional scaling on the basis of all genes. Distances in the two dimensions space were on average distorted by 11% compared to the actual 8000 dimensions gene space distances. Chernobyl Tissue Bank tumours are in bold font, French tumours in italics.

Figure 3

Top 256 most classifying genes according to GPLS/t-statistics. Chernobyl Tissue Bank samples are in red and French samples in black in the top colour bar. Data are ordered with two-way hierarchical clustering for the sake of display clarity.

Figure 4

Hierarchical clustering of transcriptional responses of the B-lymphocyte TK6 cell line to various stress agents. Expression data are from Amundson et al (2005). The responses to 200 μM of H₂O₂ and 2.5 Gy γ-radiation cluster together. Abbreviations: MMS, methyl methanesulphonate; TPA, 12-O-tetradecanoylphorbol 13-acetate; UVB, ultraviolet (280−320 nm). The suffixes ‘Exp1’ and ‘Exp2’ stand for replicated experiments.